EP2970135B1 - Pyrazolderivate als prmt1 inhibitoren und ihre verwendung - Google Patents

Pyrazolderivate als prmt1 inhibitoren und ihre verwendung Download PDF

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EP2970135B1
EP2970135B1 EP14719996.2A EP14719996A EP2970135B1 EP 2970135 B1 EP2970135 B1 EP 2970135B1 EP 14719996 A EP14719996 A EP 14719996A EP 2970135 B1 EP2970135 B1 EP 2970135B1
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alkyl
optionally substituted
certain embodiments
alkenyl
carbocyclyl
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EP2970135A1 (de
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Kevin Wayne Kuntz
Lorna Helen Mitchell
Gideon Shapiro
Richard Chesworth
Paula Ann Boriack-Sjodin
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Epizyme Inc
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Epizyme Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • compounds described herein inhibit activity of PRMT1.
  • a compound of Formula ( I ), or a pharmaceutically acceptable salt thereof is provided, for use in methods of inhibiting PRMT1 which comprise contacting PRMT1 with an effective amount of a compound of Formula ( I ), or a pharmaceutically acceptable salt thereof.
  • the PRMT1 may be purified or crude, and may be present in a cell, tissue, or a subject. Thus, such uses encompass inhibition of PRMT1 activity both in vitro and in vivo.
  • the PRMT1 is wild-type PRMT1.
  • the PRMT1 is overexpressed.
  • the PRMT1 is a mutant.
  • the PRMT1 is in a cell.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1-20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”).
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group).
  • R y is -NR B SO 2 R A or -NHSO 2 R A , wherein R A is alkoxyalkyl. In certain embodiments, R y is -NR B SO 2 R A or -NHSO 2 R A , wherein R A is optionally substituted alkenyl. In certain embodiments, R y is -NR B SO 2 R A or -NHSO 2 R A , wherein R A is unsubstituted C 1-6 alkyl. In certain embodiments, R y is -(CR z R z ) n C(O)N(R B ) 2 . In certain embodiments, R y is-CH 2 C(O)N(R B ) 2 .
  • R 6 is optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, or optionally substituted C 3-6 carbocyclyl. In certain embodiments, R 6 is optionally substituted C 1-6 alkyl. In certain embodiments, R 6 is substituted C 1-6 alkyl. In certain embodiments, R 6 is -C 1-6 alkyl-carbocyclyl. In certain embodiments, R 6 is -CH 2 -cyclopropyl or -CH 2 -cyclobutyl. In certain embodiments, R 6 is unsubstituted C 1-6 alkyl.
  • a pharmaceutical composition described herein is sterilized.
  • CremophorTM polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • polyoxyethylene ethers e.g., polyoxyethylene lauryl ether (Brij 30)
  • poly(vinyl-pyrrolidone) poly(vinyl-pyrrolidone)
  • diethylene glycol monolaurate triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • compositions suitable for administration to humans are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound described herein e.g., a compound of Formula ( I )), or a pharmaceutically acceptable salt thereof
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the subject is suffering from a PRMT1-mediated disorder.
  • the subject is susceptible to a PRMT1-mediated disorder.
  • a method of treatment for a subject in need thereof comprising the steps of determining the presence of PRMT1-mediated disorder or a gene mutation in the PRMT1 gene and treating the subject in need thereof, based on the presence of a PRMT1-mediated disorder or gene mutation in the PRMT1 gene with a therapy that includes the administration of a provided compound.
  • the subject is a cancer patient.
  • a compound provided herein is useful in treating a proliferative disorder, such as cancer.
  • inhibitors of PRMT1 are useful in treating cancers associated with ERa methylation, e.g., breast cancer.
  • PRMT1 has been shown to be involved in the regulation of leukemia development.
  • compounds described herein are useful for treating a cancer including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer ( e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer ( e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma, adrenal gland cancer
  • a compound provided herein is useful in treating metabolic disorders.
  • PRMT1 has been shown to enhance mRNA levels of FoxO1 target genes in gluconeogenesis, which results in increased hepatic glucose production, and knockdown of PRMT1 promotes inhibition of FoxO1 activity and thus inhibition of hepatic gluconeogenesis ( Choi et al., Hepatology 2012 56:1546-56 ).
  • genetic haploinsufficiency of Prmt1 has been shown to reduce blood glucose levels in mouse models.
  • the inhibition of PRMT1, e.g., by compounds described herein is beneficial in the treating of metabolic disorders, such as diabetes.
  • a provided compound is useful in treating type I diabetes.
  • a provided compound is useful in treating type II diabetes.
  • a compound provided herein is useful in treating muscular dystrophies.
  • PRMT1 methylates the nuclear poly(A)-binding protein (PABPN1) in a region located near its C-terminus ( Perreault et al., J. Biol. Chem. 2007 282:7552-62 ). This domain is involved in the aggregation of the PABPN1 protein, and abnormal aggregation of this protein is involved in the disease oculopharyngeal muscular dystrophy ( Davies et al., Int. J. Biochem. Cell. Biol. 2006 38:1457-62 ).
  • Co-engagement of the CD28 costimulatory receptor with the T cell receptor elevates PRMT1 activity and cellular protein arginine methylation, including methylation of the guanine nucleotide exchange factor Vav1 ( Blanchet et al., J. Exp. Med. 2005 202:371-377 ).
  • PRMT1 inhibitors are thus expected to diminish methylation of the guanine exchange factor Vav1, resulting in diminished IL-2 production.
  • PRMT1 is known to enhance NFkB p65-driven transcription and facilitate the transcription of p65 target genes like TNF ⁇ ( Covic et al., Embo. J. 2005 24:85-96 ).
  • pyrazole compounds of general formula V can be prepared from iodopyrazole carboxaldehydes of general formula LI as depicted in Scheme 8.
  • Protein Expression Recombinant baculovirus were generated according to Bac-to-Bac kit instructions (Life Technologies). Protein over-expression was accomplished by infecting exponentially growing High Five insect cell culture at 1.5X10 6 cell/ml with 1:100 ratio of virus. Infections were carried out at 27°C for 48 hours, harvested by centrifugation, and stored at -80°C for purification.

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Claims (16)

  1. Verbindung der Formel I
    Figure imgb0133
     oder ein pharmazeutisch unbedenkliches Salz davon, wobei
    X für N steht, Z für NR4 steht und Y für CR5 steht oder
    X für NR4 steht, Z für N steht und Y für CR5 steht oder
    X für CR5 steht, Z für NR4 steht und Y für N steht oder
    X für CR5 steht, Z für N steht und Y für NR4 steht,
    R2 für Wasserstoff, Halogen, -CN, gegebenenfalls substituiertes Alkyl, gegebenenfalls substituiertes Alkenyl, gegebenenfalls substituiertes Alkinyl, gegebenenfalls substituiertes Carbocyclyl, oder -ORA steht, wobei R2 nicht für -CF3 oder -CHF2 steht,
    R6 für Wasserstoff, Halogen, -CN, gegebenenfalls substituiertes Alkyl, gegebenenfalls substituiertes Alkenyl, gegebenenfalls substituiertes Alkinyl, gegebenenfalls substituiertes Carbocyclyl, oder -ORA steht, wobei R6 nicht für -CF3 oder -CHF2 steht,
    RA jeweils unabhängig aus der aus Wasserstoff, gegebenenfalls substituiertem Alkyl, gegebenenfalls substituiertem Alkenyl, gegebenenfalls substituiertem Alkinyl, gegebenenfalls substituiertem Carbocyclyl, gegebenenfalls substituiertem Heterocyclyl, gegebenenfalls substituiertem Aryl, gegebenenfalls substituiertem Heteroaryl, einer Sauerstoffschutzgruppe, wenn an ein Sauerstoffatom gebunden, und einer Schwefelschutzgruppe, wenn an ein Schwefelatom gebunden, bestehenden Gruppe ausgewählt ist,
    RB jeweils unabhängig aus der aus Wasserstoff, gegebenenfalls substituiertem Alkyl, gegebenenfalls substituiertem Alkenyl, gegebenenfalls substituiertem Alkinyl, gegebenenfalls substituiertem Carbocyclyl, gegebenenfalls substituiertem Heterocyclyl, gegebenenfalls substituiertem Aryl, gegebenenfalls substituiertem Heteroaryl und einer Stickstoffschutzgruppe bestehenden Gruppe ausgewählt ist oder zwei RB-Gruppen zusammen mit den dazwischenliegenden Atomen einen gegebenenfalls substituierten heterocyclischen Ring bilden,
    R3 für Wasserstoff, C1-4-Alkyl oder C3-4-Cycloalkyl steht,
    R4 für Wasserstoff, gegebenenfalls substituiertes C1-6-Alkyl, gegebenenfalls substituiertes C2-6-Alkenyl, gegebenenfalls substituiertes C2-6-Alkinyl, gegebenenfalls substituiertes C3-7-Cycloalkyl, gegebenenfalls substituiertes 4- bis 7-gliedriges Heterocyclyl oder gegebenenfalls substituiertes C1-4-Alkyl-Cy steht,
    Cy für gegebenenfalls substituiertes C3-7-Cycloalkyl, gegebenenfalls substituiertes 4- bis 7-gliedriges Heterocyclyl, gegebenenfalls substituiertes Aryl oder gegebenenfalls substituiertes Heteroaryl steht,
    R5 für Wasserstoff, Halogen, -CN, gegebenenfalls substituiertes C1-4-Alkyl oder gegebenenfalls C3-4-Cycloalkyl steht,
    Rx für gegebenenfalls substituiertes C1-4-Alkyl oder gegebenenfalls substituiertes C3-4-Cycloalkyl steht, Ry für -NRBC(O)RA, -NRBSO2RA oder -(CRzRz)nC(O)N(RB)2 steht,
    Rz jeweils unabhängig für Wasserstoff oder Fluor steht, und n für 0, 1, 2, 3 oder 4 steht,
    wobei, wenn nicht anders angegeben,
    sich Heterocyclyl bzw. heterocyclisch auf einen Rest eines 3- bis 10-gliedrigen nichtaromatischen Ringsystems mit Ringkohlenstoffatomen und 1-4 Ringheteroatomen bezieht, wobei die Heteroatome jeweils unabhängig voneinander aus Stickstoff, Sauerstoff und Schwefel ausgewählt sind,
    sich Carbocyclyl bzw. carbocyclisch auf einen Rest einer nichtaromatischen cyclischen Kohlenwasserstoffgruppe mit 3 bis 10 Ringkohlenstoffatomen und 0 Heteroatomen im nichtaromatischen Ringsystem bezieht,
    sich Aryl auf einen Rest eines monocyclischen oder polycyclischen aromatischen Ringsystems mit 6-14 Ringkohlenstoffatomen und 0 Heteroatomen im aromatischen Ringsystem bezieht und
    sich Heteroaryl auf einen Rest eines 5- bis 10-gliedrigen monocyclischen oder bicyclischen 4n+2-aromatischen Ringsystems mit Ringkohlenstoffatomen und 1-4 Ringheteroatomen im aromatischen Ringsystem bezieht, wobei die Heteroatome jeweils unabhängig voneinander aus Stickstoff, Sauerstoff und Schwefel ausgewählt sind,
    sich Alkyl auf einen Rest einer geradkettigen oder verzweigten gesättigten Kohlenwasserstoffgruppe mit 1 bis 20 Kohlenstoffatomen bezieht,
    sich Alkenyl auf einen Rest einer geradkettigen oder verzweigten Kohlenwasserstoffgruppe mit 2 bis 20 Kohlenstoffatomen und einer oder mehreren Kohlenstoff-Kohlenstoff-Doppelbindungen bezieht,
    sich Alkenyl auf einen Rest einer geradkettigen oder verzweigten Kohlenwasserstoffgruppe mit 2 bis 20 Kohlenstoffatomen und einer oder mehreren Kohlenstoff-Kohlenstoff-Dreifachbindungen bezieht,
    fakultative Kohlenstoffatom-Substituenten aus Halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa,-ON(Rbb)2, -N(Rbb)2, -N(Rbb)3 +X-, -N(ORcc)Rbb, -SH, -SRaa,-SSRcc, -C(=O)Raa, -CO2H, -CHO, -C(ORcc)2,-CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2,-OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa,-OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2,-NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa,-SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa,-OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3, -C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa,-SC(=O)ORaa, -SC(=O)Raa, -P(=O)2Raa, -OP(=O)2Raa,-P(=O)(Raa)2, -OP(=O)(Raa)2, -OP(=O)(ORcc)2, -P(=O)2N(Rbb)2, -OP(=O)2N(Rbb)2, -P(=O)(NRbb)2, -OP(=O)(NRbb)2,-NRbbP(=O)(ORcc)2, -NRbbP(=O)(NRbb)2, -P(Rcc)2, -P(Rcc)3,-OP(Rcc)2, -OP(Rcc)3, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), C1-10-Alkyl, C1-10-Perhalogenalkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Carbocyclyl, 3- bis 14-gliedriges Heterocyclyl, C6-14-Aryl und 5- bis 14-gliedriges Heteroaryl ausgewählt sind, wobei Alkyl, Alkenyl, Alkinyl, Carbocyclyl, Heterocyclyl, Aryl und Heteroaryl jeweils unabhängig durch 0, 1, 2, 3, 4 oder 5 Rdd-Gruppen substituiert sind,
    oder zwei geminale Wasserstoffatome an einem Kohlenstoffatom durch die Gruppe =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb oder =NORcc ersetzt sind,
    Raa bei jedem Auftreten unabhängig aus C1-10-Alkyl, C1-10-Perhalogenalkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Carbocyclyl, 3- bis 14-gliedrigem Heterocyclyl, C6-14-Aryl und 5- bis 14-gliedrigem Heteroaryl ausgewählt ist oder zwei Raa-Gruppen unter Bildung eines 3- bis 14-gliedrigen Heterocyclyl- oder 5- bis 14-gliedrigen Heteroarylrings miteinander verbunden sind, wobei Alkyl, Alkenyl, Alkinyl, Carbocyclyl, Heterocyclyl, Aryl und Heteroaryl jeweils unabhängig durch 0, 1, 2, 3, 4 oder 5 Rdd-Gruppen substituiert sind,
    Rbb bei jedem Auftreten unabhängig aus Wasserstoff, -OH, -ORaa, -N(Rcc)2, -CN, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)2N(Rcc)2, -P(=O)(NRcc)2, C1-10-Alkyl, C1-10-Perhalogenalkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Carbocyclyl, 3- bis 14-gliedrigem Heterocyclyl, C6-14-Aryl und 5- bis 14-gliedrigem Heteroaryl ausgewählt ist oder zwei Rbb-Gruppen unter Bildung eines 3- bis 14-gliedrigen Heterocyclyl- oder 5-bis 14-gliedrigen Heteroarylrings miteinander verbunden sind, wobei Alkyl, Alkenyl, Alkinyl, Carbocyclyl, Heterocyclyl, Aryl und Heteroaryl jeweils unabhängig durch 0, 1, 2, 3, 4 oder 5 Rdd-Gruppen substituiert sind,
    Rcc bei jedem Auftreten unabhängig aus Wasserstoff, C1-10-Alkyl, C1-10-Perhalogenalkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Carbocyclyl, 3- bis 14-gliedrigem Heterocyclyl, C6-14-Aryl und 5- bis 14-gliedrigem Heteroaryl ausgewählt ist oder zwei Rcc-Gruppen unter Bildung eines 3- bis 14-gliedrigen Heterocyclyl- oder 5-bis 14-gliedrigen Heteroarylrings miteinander verbunden sind, wobei Alkyl, Alkenyl, Alkinyl, Carbocyclyl, Heterocyclyl, Aryl und Heteroaryl jeweils unabhängig durch 0, 1, 2, 3, 4 oder 5 Rdd-Gruppen substituiert sind,
    Rdd bei jedem Auftreten unabhängig aus Halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3 +X-, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee,-C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2,-NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree,-S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)2Ree, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-6-Alkyl, C1-6-Perhalogenalkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-10-Carbocyclyl, 3- bis 10-gliedrigem Heterocyclyl, C6-10-Aryl, 5- bis 10-gliedrigem Heteroaryl ausgewählt ist, wobei Alkyl, Alkenyl, Alkinyl, Carbocyclyl, Heterocyclyl, Aryl und Heteroaryl jeweils unabhängig durch 0, 1, 2, 3, 4 oder 5 Rgg-Gruppen substituiert sind, oder zwei geminale Rdd-Substituenten unter Bildung von =O oder =S miteinander verbunden sein können,
    Ree bei jedem Auftreten unabhängig aus C1-6-Alkyl, C1-6-Perhalogenalkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-10-Carbocyclyl, C6-10-Aryl, 3- bis 10-gliedrigem Heterocyclyl und 3- bis 10-gliedrigem Heteroaryl ausgewählt ist, wobei Alkyl, Alkenyl, Alkinyl, Carbocyclyl, Heterocyclyl, Aryl und Heteroaryl jeweils unabhängig durch 0, 1, 2, 3, 4 oder 5 Rgg-Gruppen substituiert sind,
    Rff bei jedem Auftreten unabhängig aus Wasserstoff, C1-6-Alkyl, C1-6-Perhalogenalkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-10-Carbocyclyl, 3- bis 10-gliedrigem Heterocyclyl, C6-10-Aryl und 5- bis 10-gliedrigem Heteroaryl ausgewählt ist oder zwei Rff-Gruppen unter Bildung eines 3- bis 14-gliedrigen Heterocyclyl- oder 5-bis 14-gliedrigen Heteroarylrings miteinander verbunden sind, wobei Alkyl, Alkenyl, Alkinyl, Carbocyclyl, Heterocyclyl, Aryl und Heteroaryl jeweils unabhängig durch 0, 1, 2, 3, 4 oder 5 Rgg-Gruppen substituiert sind, und
    Rgg bei jedem Auftreten unabhängig für Halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -O(C1-6-Alkyl), -ON (C1-6-Alkyl)2, -N(C1-6-Alkyl)2, -N(C1-6-Alkyl)3 +X-, -NH(C1-6-Alkyl)2 +X-, -NH2(C1-6-Alkyl)+X-, -NH3 +X-, -N(O(C1-6-Alkyl))(C1-6-alkyl), -N(OH)(C1-6-Alkyl), -NH(OH), -SH, -SC1-6-Alkyl, -SS(C1-6-Alkyl), -C(=O)(C1-6-Alkyl),-CO2H, -CO2(C1-6-Alkyl), -OC(=O)(C1-6-Alkyl), -OCO2(C1-6-Alkyl), -C(=O)NH2, -C(=O)N(C1-6-Alkyl)2, -OC(=O)NH(C1-6-Alkyl), -NHC(=O)(C1-6-Alkyl), -N(C1-6-Alkyl)C(=O)(C1-6-alkyl), -NHCO2(C1-6-Alkyl), -NHC(=O)N(C1-6-Alkyl)2,-NHC(=O)NH(C1-6-Alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6-Alkyl), -OC(=NH)(C1-6-Alkyl), -OC(=NH)OC1-6-Alkyl, -C(=NH) N(C1-6-Alkyl) 2, -C(=NH)NH(C1-6-Alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6-Alkyl)2, -OC(NH)NH(C1-6-Alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6-Alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6-Alkyl), -SO2N(C1-6-Alkyl)2, -SO2NH(C1-6-Alkyl), -SO2NH2, -SO2C1-6-Alkyl, -SO2OC1-6-Alkyl, -OSO2C1-6-Alkyl, -SOC1-6-Alkyl, -Si(C1-6-Alkyl)3, -OSi(C1-6-Alkyl)3, -C(=S)N(C1-6-Alkyl)2, C(=S)NH(C1-6-Alkyl), C(=S)NH2, -C(=O)S(C1-6-Alkyl),-C(=S)S(C1-6-Alkyl), -SC(=S)S(C1-6-Alkyl), -P(=O)2(C1-6-Alkyl), -P(=O)(C1-6-Alkyl)2, -OP(=O)(C1-6-Alkyl)2, -OP(=O)(O(C1-6-Alkyl))2, C1-6-Alkyl, C1-6-Perhalogenalkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-10-Carbocyclyl, C6-10-Aryl, 3-bis 10-gliedriges Heterocyclyl, 5- bis 10-gliedriges Heteroaryl steht, oder zwei geminale Rgg-Substituenten unter Bildung von =O oder =S miteinander verbunden sein können, wobei X- für ein Gegenion steht, und
    fakultative Stickstoffatom-Substituenten aus Wasserstoff, -OH, -ORaa, -N(Rcc)2, -CN, -C(=O)Raa,-C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa,-C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa,-C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, -P(=O)2Raa,-P(=O)(Raa)2, -P(=O)2N(Rcc)2, -P(=O)(NRcc)2, C1-10-Alkyl, C1-10-Perhalogenalkyl, C2-10-Alkenyl, C2-10-Alkinyl, C3-10-Carbocyclyl, 3- bis 14-gliedriges Heterocyclyl, C6-14-Aryl und 5- bis 14-gliedriges Heteroaryl ausgewählt sind oder zwei an ein Stickstoffatom gebundene Rcc-Gruppen unter Bildung eines 3- bis 14-gliedrigen Heterocyclyl- oder 5-bis 14-gliedrigen Heteroarylrings miteinander verbunden sind, wobei Alkyl, Alkenyl, Alkinyl, Carbocyclyl, Heterocyclyl, Aryl und Heteroaryl jeweils unabhängig durch 0, 1, 2, 3, 4 oder 5 Rdd-Gruppen substituiert sind und wobei Raa, Rbb, Rcc und Rdd wie oben definiert sind.
  2. Verbindung nach Anspruch 1, wobei Ry für -NHC(O)RA steht.
  3. Verbindung nach Anspruch 1, wobei die Verbindung die Formel (II) aufweist:
    Figure imgb0134
     oder ein pharmazeutisch unbedenkliches Salz davon, oder wobei die Verbindung die Formel (IV) aufweist:
    Figure imgb0135
     oder ein pharmazeutisch unbedenkliches Salz davon.
  4. Verbindung nach einem der Ansprüche 1-3, wobei R2 für Wasserstoff steht.
  5. Verbindung nach einem der Ansprüche 1-4, wobei R6 für Wasserstoff steht.
  6. Verbindung nach einem der Ansprüche 1-5, wobei R3 für Methyl steht.
  7. Verbindung nach einem der Ansprüche 1-6, wobei R4 für Wasserstoff steht.
  8. Verbindung nach einem Ansprüche 1-7, wobei R5 für Wasserstoff steht.
  9. Verbindung nach einem der Ansprüche 1-8, wobei RX für Methyl steht.
  10. Verbindung nach Anspruch 1, ausgewählt aus der Gruppe bestehend aus den folgenden Verbindungen oder einem pharmazeutisch unbedenklichen Salz davon:
    Figure imgb0136
    Figure imgb0137
    Figure imgb0138
    Figure imgb0139
    Figure imgb0140
    Figure imgb0141
    Figure imgb0142
    Figure imgb0143
    Figure imgb0144
    Figure imgb0145
    Figure imgb0146
    Figure imgb0147
    Figure imgb0148
    Figure imgb0149
  11. Verbindung:
    Figure imgb0150
     oder ein pharmazeutisch unbedenkliches Salz davon.
  12. Pharmazeutische Zusammensetzung, umfassend eine Verbindung nach einem der Ansprüche 1-11 oder ein pharmazeutisch unbedenkliches Salz davon und einen pharmazeutisch unbedenklichen Exzipienten.
  13. Verbindung nach einem der Ansprüche 1-11 oder pharmazeutisch unbedenkliches Salz davon oder pharmazeutische Zusammensetzung nach Anspruch 12 zur Verwendung bei der Behandlung einer durch PRMT1-vermittelten Störung.
  14. Verbindung nach einem der Ansprüche 1-11 oder pharmazeutisch unbedenkliches Salz davon oder pharmazeutische Zusammensetzung nach Anspruch 12 zur Verwendung bei der Behandlung einer proliferativen Störung, einer neurologischen Störung, einer Muskeldystrophie, einer Autoimmunerkrankung, einer Gefäßerkrankung oder einer Stoffwechselkrankheit.
  15. Verbindung nach einem der Ansprüche 1-11 oder pharmazeutisch unbedenkliches Salz davon oder pharmazeutische Zusammensetzung nach Anspruch 12 zur Verwendung nach Anspruch 14, wobei es sich bei der proliferativen Störung um Krebs handelt.
  16. Verbindung nach einem der Ansprüche 1-11 oder pharmazeutisch unbedenkliches Salz davon oder pharmazeutische Zusammensetzung nach Anspruch 12 zur Verwendung nach Anspruch 15, wobei es sich bei der Krebserkrankung um Brustkrebs, Prostatakrebs, Lungenkrebs, Kolorektalkrebs, Blasenkrebs, Nierenkrebs, Leukämie oder Lymphom handelt.
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US9475776B2 (en) 2016-10-25
US9023883B2 (en) 2015-05-05
US20150284334A1 (en) 2015-10-08
US20170233347A1 (en) 2017-08-17
WO2014144659A1 (en) 2014-09-18
EP2970135A1 (de) 2016-01-20
US20180265478A1 (en) 2018-09-20
US9868703B2 (en) 2018-01-16
US10227307B2 (en) 2019-03-12
US20140288141A1 (en) 2014-09-25

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